Lipid mediators are thought to contribute to a wide variety of pathophysiologic effects in the lung. Such molecules include arachidonate derivatives, i.e., the eicosanoids (5-lipoxygenase and cyclooxygenase pathways), and the ether phospholipid, platelet activating factor (PAF). Reasonable evidence has suggested that inflammatory cells and cells within the lung tissue itself communicate via such lipid mediators and that the progression and outcome of inflammation depends in part on the synthesis and disposition of these classes of compounds. Accordingly, the overall objective of this program project is to investigate the regulation of lipid mediator biosynthesis and action. Specific objectives include: Characterization of neutrophil-platelet interactions in the production of lipid mediators with emphasis on priming and adhesion, novel integrin signaling and the modulatory role of extracellular albumin in plasma, inflammatory exudates and pulmonary inflammation. Investigation of the signal transduction mechanisms involved in priming for generation of eicosanoids and oxidants. A central hypothesis is the critical involvement of lipid remodeling enzymes and their effects on the membrane. Determination of the mechanisms governing transbilayer movement of phospholipids in membranes with particular emphasis on intracellular polyamines and oxidants. Modulation of these regulatory processes is suggested to participate in altered signal transduction, adhesion and initiation of coagulation. Detailed study of the cytoplasmic 85kDa PLA2. This enzyme is suggested to play a critical role in the first step of lipid mediator production. Emphasis will be placed on the role of phosphorylation in its activation and translocation to the membrane as well as on the kinases responsible. Structural and functional investigation of the products resulting from the action of oxidants on membrane phospholipids. A novel group of compounds termed isoeicosanoids, with potential biological activity on cell surface receptors, will receive particular attention. This program brings together investigators experienced in cell biology, signal transduction, inflammation, pharmacology, physiology, lipid biochemistry, analytical chemistry, and clinical pulmonary medicine. This combination of structural, cellular, and physiologic approaches to a detailed analysis of the production of lipid mediators in the lung is felt to represent an important step in developing the ability to select control lipid mediator production and also eliminate pathologic events mediated by these molecules in vivo.